The objectives of this proposal are to determine factors which regulate the hepatic metabolism of ethanol and acetaldehyde, and to investigate biochemicl mechanisms which are responsible for alterations in hepatic metabolism by ethanol and acetaldehyde. We plan to continue studies of factors which contribute to the metabolic adaptation found after chronic ethanol consumption, especially with regard to the role os the microsomal alcohol oxidizing system and the possible role of a hypermetabolic state. Studies to indicate that t-butyl alcohol is not metabolically inert will be carried out. Studies concerning the role of hydroxyl radicals in the microsomal pathoway for oxidizing alcohols will be continued in order to determine the molecular mechanism responsible for the oxidation of ethanol by microsomes. Techniques to evaluate the generation of oxygen radicals by microsomes, by lever cells and by purified cytochrome P-450 fractions will be introduced. Mechanisms involved in the production of these radicals, and the influence of ethanol on oxygen radical production will be determined. Experiments to evaluate the oxidation of OH scavengers in vivo will be initiated. Such studies may be of value in understanding the interaction between ethanol and drugs in the liver. The role of acetaldehyde in the actions of ethanol on selected hepatic functions such as gluconeogeneisis, drug metabolism and fatty acid oxidation will be investigated, especially with regard to the possibility that hepatocellular functions may be more sensitive to acetaldehyde after chronic ethanol consumption. Studies on the regulation of acetaldehyde metabolism will be continued to determine if the metabolism nd release of acetaldehyde for the liver cell is altered by chronic consumption of ethanol. Since thanol is the most widely used drug in the world, investigations of the biochemical mechanisms which contribute to the pathogenesis of the alcohol-induced liver injury may localize sites of injury at the molecular level and provide a rationale for attempts to prevent or ameliorate the actions of ethanol.